Gamma-crystalline form of ivabradine hydrochloride, a process for its preparation and pharmaceutical compositions containing it

ABSTRACT

A γ-Crystalline form of ivabradine hydrochloride of formula (I):  
                 
characterised by its powder X-ray diffraction data. Medicinal products containing the same which are useful as bradycardics.

The present invention relates to the new γ-crystalline form of ivabradine hydrochloride of formula (I), to a process for its preparation and to pharmaceutical compositions containing it.

Ivabradine, and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have very valuable pharmacological and therapeutic properties, especially bradycardic properties, making those compounds useful in the treatment or prevention of various clinical situations of myocardial ischaemia such as angina pectoris, myocardial infarct and associated rhythm disturbances, and also in various pathologies involving rhythm disturbances, especially supraventricular rhythm disturbances, and in heart failure.

The preparation and therapeutic use of ivabradine and addition salts thereof with a pharmaceutically acceptable acid, and more especially its hydrochloride, have been described in the European patent specification EP 0 534 859.

In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light or oxygen level.

The patent specification EP 0 534 859 describes a synthesis process for ivabradine and its hydrochloride. However, that document does not specify the conditions for obtaining ivabradine in a form that exhibits those characteristics in a reproducible manner.

The Applicant has now found that a particular salt of ivabradine, the hydrochloride, can be obtained in a crystalline form that is well defined and that exhibits valuable characteristics of stability and processability.

More specifically, the present invention relates to the γ-crystalline form of ivabradine hydrochloride, which is characterised by the following powder X-ray diffraction diagram measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts x degrees), ray width at half-weight (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Angle Interplanar Ray 2 theta Height Area FWHM distance no. (degrees) (counts) (counts × degrees) (degrees) (Å)  1 4.2 1456 144 0.1004 20.762  2 6.9 125 99 0.8029 12.880  3 8.4 182 18 0.1004 10.503  4 10.7 240 32 0.1338 8.249  5 11.3 74 15 0.2007 7.858  6 12.0 644 64 0.1004 7.392  7 12.5 1476 219 0.1506 7.060  8 13.4 2691 400 0.1506 6.612  9 14.5 541 80 0.1506 6.119 10 14.8 104 17 0.1673 5.981 11 15.9 815 67 0.0836 5.559 12 16.3 501 74 0.1506 5.419 13 17.0 1168 154 0.1338 5.210 14 17.9 430 43 0.1004 4.962 15 19.0 667 121 0.184 4.672 16 19.8 527 104 0.2007 4.483 17 20.2 726 144 0.2007 4.392 18 20.5 282 28 0.1004 4.323 19 21.1 2255 260 0.1171 4.208 20 21.4 694 68 0.1004 4.147 21 21.6 744 86 0.1171 4.111 22 22.3 175 35 0.2007 3.987 23 23.5 310 61 0.2007 3.784 24 24.2 1635 270 0.1673 3.683 25 24.5 1335 220 0.1673 3.625 26 24.9 523 95 0.184 3.568 27 25.5 657 130 0.2007 3.485 28 26.0 933 154 0.1673 3.431 29 26.4 1549 230 0.1506 3.380 30 26.8 419 83 0.2007 3.323 31 27.3 350 69 0.2007 3.267 32 28.0 1108 146 0.1338 3.186 33 29.1 144 19 0.1338 3.066

The invention relates also to a process for the preparation of the γ-crystalline form of ivabradine hydrochloride, which process is characterised in that a mixture of ivabradine hydrochloride and 2-ethoxyethanol, a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallisation is complete, and the product is collected by filtration.

In the crystallisation process according to the invention it is possible to use ivabradine hydrochloride obtained by any process, for example ivabradine hydrochloride obtained by the preparation process described in patent specification EP 0 534 859.

The solution may advantageously be seeded during the cooling step.

The invention relates also to pharmaceutical compositions comprising as active ingredient the γ-crystalline form of ivabradine hydrochloride together with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragées, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions.

The useful dosage can be varied according to the nature and severity of the disorder, the administration route and the age and weight of the patient. That dosage varies from 1 to 500 mg per day in one or more administrations.

The following Examples illustrate the invention.

The X-ray powder diffraction spectrum was measured under the following experimental conditions:

PANalytical X'Pert Pro diffractometer, X'Celerator detector, temperature-regulated chamber,

voltage 45 kV, intensity 40 mA,

mounting θ-θ,

nickel (Kβ) filter,

incident-beam and diffracted-beam Soller slit: 0.04 rad,

fixed angle of divergence slits: ⅛°,

mask: 10 mm,

antiscatter slit: ¼°,

measurement mode: continuous from 3° to 30°, in increments of 0.017°,

measurement time per step: 19.7 s,

total time: 4 min 32 s,

measurement speed: 0.108°/s,

measurement temperature: ambient.

EXAMPLE 1 γ-Crystalline Form of Ivabradine Hydrochloride

40 ml of 2-ethoxyethanol are preheated to 80° C., and then 8.4 g of ivabradine hydrochloride obtained according to the process described in the patent specification EP 0 534 859 are added in portions, with stirring, and the mixture is heated at 80° C. until dissolution is complete. After returning to ambient temperature, the solution is stored for 8 days, and then the crystals formed are collected by filtration and rinsed with cyclohexane.

The water content of the crystals obtained, determined by coulometry, is 3.5%, which corresponds to a monohydrate.

X-Ray Powder Diffraction Diagram:

The X-ray powder diffraction profile (diffraction angles) of the γ-form of ivabradine hydrochloride is given by the significant rays collated in the following table: Angle Interplanar Ray 2 theta Height Area FWHM distance no. (degrees) (counts) (counts × degrees) (degrees) (Å)  1 4.2 1456 144 0.1004 20.762  2 6.9 125 99 0.8029 12.880  3 8.4 182 18 0.1004 10.503  4 10.7 240 32 0.1338 8.249  5 11.3 74 15 0.2007 7.858  6 12.0 644 64 0.1004 7.392  7 12.5 1476 219 0.1506 7.060  8 13.4 2691 400 0.1506 6.612  9 14.5 541 80 0.1506 6.119 10 14.8 104 17 0.1673 5.981 11 15.9 815 67 0.0836 5.559 12 16.3 501 74 0.1506 5.419 13 17.0 1168 154 0.1338 5.210 14 17.9 430 43 0.1004 4.962 15 19.0 667 121 0.184 4.672 16 19.8 527 104 0.2007 4.483 17 20.2 726 144 0.2007 4.392 18 20.5 282 28 0.1004 4.323 19 21.1 2255 260 0.1171 4.208 20 21.4 694 68 0.1004 4.147 21 21.6 744 86 0.1171 4.111 22 22.3 175 35 0.2007 3.987 23 23.5 310 61 0.2007 3.784 24 24.2 1635 270 0.1673 3.683 25 24.5 1335 220 0.1673 3.625 26 24.9 523 95 0.184 3.568 27 25.5 657 130 0.2007 3.485 28 26.0 933 154 0.1673 3.431 29 26.4 1549 230 0.1506 3.380 30 26.8 419 83 0.2007 3.323 31 27.3 350 69 0.2007 3.267 32 28.0 1108 146 0.1338 3.186 33 29.1 144 19 0.1338 3.066

EXAMPLE 2 Pharmaceutical Composition

Formula for the preparation of 1000 tablets each containing 5 mg of ivabradine base: Compound of Example 1 5.39 g Maize starch 20 g Anhydrous colloidal silica 0.2 g Mannitol 63.91 g PVP 10 g Magnesium stearate 0.5 g 

1. A γ-Crystalline form of ivabradine hydrochloride of formula (I):

exhibiting essentially the following powder X-ray diffraction data, measured using a PANalytical X'Pert Pro diffractometer together with an X'Celerator detector and expressed in terms of ray position (Bragg's angle 2 theta, expressed in degrees), ray height (expressed in counts), ray area (expressed in counts x degrees), ray width at half-height (“FWHM”, expressed in degrees) and interplanar distance d (expressed in Å): Angle Interplanar Ray 2 theta Height Area FWHM distance no. (degrees) (counts) (counts × degrees) (degrees) (Å)  1 4.2 1456 144 0.1004 20.762  2 6.9 125 99 0.8029 12.880  3 8.4 182 18 0.1004 10.503  4 10.7 240 32 0.1338 8.249  5 11.3 74 15 0.2007 7.858  6 12.0 644 64 0.1004 7.392  7 12.5 1476 219 0.1506 7.060  8 13.4 2691 400 0.1506 6.612  9 14.5 541 80 0.1506 6.119 10 14.8 104 17 0.1673 5.981 11 15.9 815 67 0.0836 5.559 12 16.3 501 74 0.1506 5.419 13 17.0 1168 154 0.1338 5.210 14 17.9 430 43 0.1004 4.962 15 19.0 667 121 0.184 4.672 16 19.8 527 104 0.2007 4.483 17 20.2 726 144 0.2007 4.392 18 20.5 282 28 0.1004 4.323 19 21.1 2255 260 0.1171 4.208 20 21.4 694 68 0.1004 4.147 21 21.6 744 86 0.1171 4.111 22 22.3 175 35 0.2007 3.987 23 23.5 310 61 0.2007 3.784 24 24.2 1635 270 0.1673 3.683 25 24.5 1335 220 0.1673 3.625 26 24.9 523 95 0.184 3.568 27 25.5 657 130 0.2007 3.485 28 26.0 933 154 0.1673 3.431 29 26.4 1549 230 0.1506 3.380 30 26.8 419 83 0.2007 3.323 31 27.3 350 69 0.2007 3.267 32 28.0 1108 146 0.1338 3.186 33 29.1 144 19 0.1338 3.066


2. A process for the preparation of the γ-crystalline form of ivabradine hydrochloride of claim 1, wherein a mixture of ivabradine hydrochloride and 2-ethoxyethanol, a mixture of ivabradine hydrochloride, 2-ethoxyethanol and water, or a mixture of ivabradine hydrochloride, ethanol and water is heated until dissolution is complete and is then cooled until crystallisation is complete, and the product thus obtained is collected by filtration.
 3. The process of claim 2, wherein the solution of ivabradine hydrochloride is seeded during the cooling step.
 4. A pharmaceutical composition comprising as active ingredient the γ-crystalline form of ivabradine hydrochloride of claim 1, in combination with one or more pharmaceutically acceptable, inert, non-toxic carriers.
 5. A method for treating or preventing a condition requiring a bradycardic, such method comprising administering to a living animal body, including a human, a therapeutically effective amount of a γ-crystalline form of ivabradine hydrochloride of claim
 1. 6. A method for treating or preventing clinical situations of myocardial ischaemia and/or a condition involving rhythm disturbances, such method comprising administering to a living animal body, including a human, a therapeutically effective amount of a γ-crystalline form of ivabradine hydrochloride of claim
 1. 7. The method of claim 6, wherein the clinical situation of myocardial ischaemia is selected from angina pectioris and myocardial infarct and associated rhythm disturbances.
 8. The method of claim 6, wherein the condition involving rhythm disturbances is selected from supra ventricular rhythm disturbances and heart failure. 